Effect of protein, unsaturated fat, and carbohydrate intakes on plasma apolipoprotein B and VLDL and...

Effect of protein, unsaturated fat, and carbohydrate intakes onplasma apolipoprotein B and VLDL and LDL containingapolipoprotein C-III: results from the OmniHeart Trial2

Jeremy D Furtado, Hannia Campos, Lawrence J Appel, Edgar R Miller, Nancy Laranjo,Vincent J Carey, and Frank M SacksHarvard School of Public Health, Boston, MA (JDF, HC, and FMS); the Johns Hopkins University,Baltimore, MD (LJP and ERM); and the Channing Laboratory, Department of Medicine, Brighamand Women's Hospital and Harvard Medical School, Boston, MA (NL, VJC, and FMS).

AbstractBackground—Plasma apolipoprotein B (apo B) and VLDL and LDL with apolipoprotein C-III(apo C-III) are independent risk factors for cardiovascular disease (CVD). Dietary intake affectslipoprotein concentration and composition related to those apolipoproteins.

Objective—We studied differences in apo B lipoproteins with and without apo C-III after 3 healthydiets based on the Dietary Approaches to Stop Hypertension Trial diet.

Design—Healthy participants (n = 162) were fed each of 3 healthy diets for 6 wk in a crossoverdesign. Diets differed by emphasis of either carbohydrate (Carb), unsaturated fat (Unsat), or protein(Prot). Blood was collected at baseline and after diets for analysis.

Results—Compared with the Carb diet, the Prot diet reduced plasma apo B and triglycerides inVLDL with apo C-III (16%, P = 0.07; 11%, P = 0.05, respectively) and apo B in LDL with apo C-III (16%, P = 0.04). Compared with the Unsat diet, the Prot diet reduced triglycerides in VLDL withapo C-III (16%, P = 0.02). Compared with baseline (subjects' usual diet was higher in saturated fat),the Prot diet reduced apo B in LDL with apo C-III (11%, P = 0.05), and all 3 diets reduced plasmatotal apo B (6−10%, P < 0.05) and apo B in the major type of LDL, LDL without apo C-III (8 −10%,P < 0.01). All 3 diets reduced the ratio of apo C-III to apo E in VLDL.

Conclusions—Substituting protein for carbohydrate in the context of a healthy dietary patternreduced atherogenic apo C-III–containing LDL and its precursor, apo C-III–containing VLDL,resulting in the most favorable profile of apo B lipoproteins. In addition, compared with a typicalhigh-saturated fat diet, healthy diets that emphasize carbohydrate, protein, or unsaturated fat reduceplasma total and LDL apo B and produce a lower more metabolically favorable ratio of apo C-III toapo E.

INTRODUCTIONPlasma LDL-cholesterol and total triglyceride (TG) concentrations are established risk factorsfor cardiovascular disease (CVD). Clinical trials have shown that apolipoprotein B (apo B)–containing lipoproteins contribute to the development and progression of atheroscleroticlesions (1,2). Elevated plasma apo B is more strongly associated with vascular disease risk

2Supported by grants from the National Institutes of Health (grants HL67098, DK63214, HL68712, and RR02635). Food was generouslysupplied by The Almond Board, International Tree Nut Council, Olivio Premium Products Inc, and The Peanut Institute.Reprints not available. Address correspondence to FM Sacks, Building 1, Room 204, 665 Huntington Avenue, Boston, MA 02115. E-mail: [email protected]..

NIH Public AccessAuthor ManuscriptAm J Clin Nutr. Author manuscript; available in PMC 2009 June 1.

Published in final edited form as:Am J Clin Nutr. 2008 June ; 87(6): 1623–1630.

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factors such as abdominal obesity, dyslipidemia, hyperinsulinemia, and thrombosis than isLDL cholesterol (3), and recent evidence suggests it to be a superior predictor of CVD riskthan LDL cholesterol (4,5) or non-HDL cholesterol (6–8).

Apolipoprotein C-III (apo C-III) can be present on both apo B–containing or apolipoproteinA-I (apo A-I)–containing (ie, HDL) lipoproteins but is not integral to the basic lipoproteinparticle structure; thus, lipoproteins exist both with and without apo C-III. Apo B–containinglipoproteins with apo C-III are enriched in TGs and cholesterol and have slow clearance fromplasma. Concentration of apo C-III in VLDL and LDL is highly and independently predictiveof coronary heart disease, more so than TGs alone (9). Above all, LDL particles with apo C-III, a remnant particle produced by partial lipolysis in plasma of VLDL with apo C-III (10), isthe lipoprotein particle type most predictive of CVD in type 2 diabetes (11). Apo C-III inhibitsdirect clearance of VLDL particles from plasma, resulting in the formation of LDL. Newresearch strengthens the association between CVD and apo C-III by showing that apo C-IIIincreases the adhesion of human monocytes to endothelial cells and activates proinflammatorymolecules such as nuclear transcription factor κB in these cells (12–14)

The strong association between blood lipoproteins and CVD has fueled the investigation ofdietary effects on lipoproteins as a pathway to CVD. Variations in macronutrient intake affectlipoprotein risk factors (15–21). Replacement of saturated fat with carbohydrate, unsaturatedfat, or protein reduces LDL cholesterol, with unsaturated fat and protein having slightly moreof an effect than carbohydrate (21). Carbohydrate compared with unsaturated fat or proteinincreases TGs (21,22). However, knowledge is sparse on the effects of dietary macronutrientson atherogenic lipoprotein subfractions that are recently emerging as important risk factors forCVD.

In this setting we examined the effect of 3 healthy diets modeled after the Dietary Approachesto Stop Hypertension Trial (DASH) diet on plasma lipids and lipoproteins. The originalcarbohydrate-rich DASH diet lowers LDL cholesterol (23) and is considered the benchmarkfor US dietary recommendations. The 3 diets studied in the Optimal Macronutrient Intake Trialto Prevent Heart Disease (OmniHeart) differ from each other by their emphasis on eithercarbohydrate (Carb diet; modeled after the original DASH diet), unsaturated fat (Unsat diet),or protein (Prot diet). Because carbohydrate increases plasma TGs, we hypothesize that partialreplacement of carbohydrate with either protein or unsaturated fat will reduce TG-richlipoproteins typified by a high content of apo C-III.

SUBJECTS AND METHODSThe rationale and design of the OmniHeart trial as well as the main blood pressure and lipidresults (21) were published previously. Briefly, the OmniHeart trial is an investigator-initiatedstudy sponsored by the National Heart, Lung, and Blood Institute that used a randomized, 3-period crossover design to compare the effects of macronutrients on blood pressure and plasmalipids. Study diets were modeled on the successful DASH diet and emphasized eithercarbohydrate (Carb diet), unsaturated fats (Unsat diet), or nonmeat protein (Prot diet). TheDASH diet was chosen because it is effective at reducing diastolic and systolic blood pressures.DASH was found to lower LDL cholesterol, but it also lowered HDL cholesterol and increasedTGs, as many carbohydrate-rich diets were shown to do. In this study, we examine the effectof replacing some of the carbohydrate with unsaturated fat or protein. A detailed descriptionof these 3 diets was published previously (24) and is summarized in Table 1.

Participant recruitmentTrial participants lived in the greater Boston, MA, and greater Baltimore, MD, areas and wereadult men and women aged ≥30 y with systolic blood pressure 120−159 mm Hg, diastolic

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blood pressure < 100 mm Hg, fasting LDL cholesterol < 220 mg/dL, and TGs < 750 mg/dL.Other exclusion criteria were described previously (21). By design, we aimed to recruit 50%African Americans and 50% women. Eligibility was determined during screening visits, atwhich time a blood sample was taken for baseline measurement. The blood samples wereimmediately centrifuged to collect plasma, which was then divided into aliquots and stored at−80 °C pending analysis. Eligible participants then completed a 6-d run-in period during whichtime they were given the meals that were to be provided during the 3 diet periods. Subjectswho failed to adhere to the protocol during the run-in period were excluded.

Controlled feedingEach participant was randomly assigned 1 of 6 sequences of the 3 diets (Carb, Unsat, Prot).Each diet consisted of commonly available foods. The initial calorie content was determinedfor each participant, based on body size, sex, and physical activity level. Body weight wasmonitored daily, and calorie content of the diets was adjusted to maintain initial body weight.All meals, snacks, and beverages, except for discretionary calorie-free beverages, wereprovided to the participants. In addition, participants were requested to maintain their usualintake of alcoholic beverages, not to exceed 2 drinks/d. Participants were instructed to eat onlythe food provided and to maintain their usual levels of physical activity. Adherence wasmonitored through daily diet diaries and at their weekday visits to the study center. At the endof the fourth and sixth weeks of each diet period, blood was drawn, centrifuged, divided intoaliquots, and stored at −80 °C pending laboratory analysis. Participants then ate their usualfree-living diet for a minimum of 2 wk before beginning the next diet period. Controlled feedingtook place from April 2003 to June 2005.

Laboratory measurementsAll 162 participants who successfully completed ≥2 of the 3 diet periods were included in thelaboratory analysis. Each participant provided 4 samples for analysis, one at baseline and oneafter each of the three 6-wk diet periods. Blood samples were collected in tubes containingEDTA. The study was conducted from April 2003 to June 2005. Laboratory analysis beganMarch 2004 and was completed August 2005. Samples were submitted to the laboratory inbatches, and the batches were analyzed in the order received. Therefore, the longest possibleperiod of storage was 12 mo, with most samples stored ≤10 mo. The 4 samples were analyzedin the same batch in random order to reduce analytic variation. Analysis batches consisted of5 or 9 participants, depending on the week, and batches were completed within 5 d. Alllaboratory staff members were blinded to the diet sequences of the participants.

Immunoaffinity chromatographySamples were removed from cryogenic storage and thawed in the dark at room temperaturefor 30 min. Samples were filtered, and 700 μL filtered plasma was loaded into 20 mL Econo-Pac columns (Bio-Rad Laboratories, Hercules, CA) packed with anti–apo C-III resin(polyclonal goat anti–human apo C-III antibody bound to Sepharose 4B Resin; AcademyBiomedical Company Inc, Houston, TX). Samples and resin were incubated for 16 h at 4 °Cwith mixing. The unbound fraction was eluted from the column by gravity followed by washeswith phosphate-buffered saline. The bound fraction was then eluted from the columns with 3mol/L sodium thiocyanate in phosphate-buffered saline and was immediately desalted with theuse of PD-10 columns (GE Healthcare, Little Chalfont, United Kingdom).

The immunoaffinity columns consisted of 2.5 mL anti–apo C-III resin prepared with the useof polyclonal goat anti–human apo C-III antibody bound to Sepharose 4B Resin at a minimumconcentration of 5 mg antibody/mL resin. The highest concentration of plasma apo C-III foundin this study was ≈61 mg/dL (0.61 mg/mL). At a load volume of 0.7 mL, this is a maximumload of 0.4 mg, which is below the minimum theoretical capacity of 0.6 mg apo C-III based



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on column specifications. All columns were tested to ensure efficiency of >95% before thestart of laboratory analysis and midway through the analysis period by application of a qualitycontrol plasma sample to each column and measurement of apo C-III concentration of both theretained and unretained fractions. In addition, a separate quality control sample was includedin each sample batch that was randomly assigned to a different column each week. No columnfailures were found during this study.

UltracentrifugationThe bound and unbound fractions were ultracentrifuged to separate particles by density. VLDLwas isolated by overlaying 700 μL of sample with 300 μL of potassium bromide [with density(d) = 1.006 g/mL] aqueous solution (Sigma-Aldrich, St. Louis, MO) and spinning for 16 h at15 °C and 25 000 rpm in the outer-most row of a Beckman 25-Ti rotor with a Beckman L8−70M ultracentrifuge (Beckman Coulter, Inc, Fullerton, CA). The top 200 ± 10 μL from each tubewas collected by careful aspiration and stored at 4 °C briefly, pending same-day analysis oflipids and apolipoproteins while the next ultracentrifugation step for LDL was prepared. LDLwas isolated by overlaying the plasma remaining after VLDL aspiration with 34% potassiumbromide solution to produce a final density of 1.063 g/mL and spinning for 24 h under the sameconditions as for VLDL isolation. The top 300 ± 10 μL from each was collected by aspiration.Three density fractions of plasma were thus isolated: <1.006 g/mL (VLDL), 1.006 g/mL to<1.063 g/mL (LDL), and > 1.063 g/mL (very dense LDL, HDL, plasma proteins). The productsof the immunoaffinity chromatography followed by density fractionation byultracentrifugation were VLDL without apo C-III, VLDL with apo C-III, LDL without apo C-III, LDL with apo C-III, d > 1.063 g/mL lipoproteins without apo C-III, and d > 1.063 g/mLlipoproteins with apo C-III.

Determination of lipids and apolipoproteinsSandwich enzyme-linked immunoabsorbent assay (ELISA) procedures with the use of affinity-purified antibodies (Academy Biomedical Company Inc) were performed to determine theconcentrations of apo B, apo C-III, and apolipoprotein E (apo E) in whole plasma and thelipoprotein fractions. TGs and cholesterol were determined enzymatically (Thermo Scientific,Waltham, MA). Liquid transfer for 96-well plate loading and ELISA dilutions were handledrobotically with a Multiprobe II (Perkin-Elmer, Waltham, MA) to minimize pipetting error.Both ELISA and lipid plates were read with a BioTek ELx808iu 96-well plate reader controlledby KCJUNIOR software (BioTek, Winooski, VT). All assays were completed in triplicate, andany sample with an intraassay CV > 15% was repeated. Final data were exported to MicrosoftEXCEL (Microsoft, Reman, WA) for analysis and database management.

EthicsThe study protocol was approved by the Institutional Review Boards at all affiliated institutions(Johns Hopkins University, Brigham & Women's Hospital, and the Harvard School of PublicHealth).

StatisticsThe primary outcome was apo B concentration in whole plasma and in the lipoproteinsubfractions. Cholesterol, TG, apo C-III, and apo E concentrations were examined as secondaryoutcomes. The main comparisons in this study were made among the Carb, Unsat, and Protdiets, in particular the Prot-Carb diets and the Unsat-Carb diets; the Unsat-Prot diet was ofsecondary interest and was mathematically contained in the other 2 differences. Paired t testsof the between-diet differences were used to assess the differential effects of the diets.Secondarily, we examined the change from baseline elicited by each diet with paired t tests ofthe difference between baseline and postdiet samples. Analyses were performed with the use



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of SAS version 9.1 (SAS Institute Inc, Cary, NC). The t tests were all 2-sided, and statisticalsignificance was defined as P ≤ 0.05. We did not adjust P values for multiple comparisonsbecause there is no consensus for adjustment when many of the outcome variables (lipoproteinsubtypes) examined are highly interrelated with the others. Our analysis produced patterns ofsignificance that corroborate one another, which reduces the risk of reporting significance offalse positives because of the sheer number of tests performed. Furthermore, the “proc mixed”procedure, which performs a global test reducing the risk of type I error, was performed toconfirm the findings of the paired t tests. For a study such as this with many subsamples perparticipant, there are randomly occurring missing values, stemming from limitations inlaboratory technology, eg, detection limits, lack of sufficient sample, or out-of-range value.Imputation of these missing data points must be handled differently for each different reasonfor the missingness. Choosing a single imputation strategy for all missing data introduces noise.Therefore, for this analysis no missing data were imputed. Instead, the t tests for each outcomeare performed with the use of subsets of the data that exclude any subjects' missing data forthat particular outcome. Although this reduces power compared with an analysis of allparticipants with imputation, it avoids regression to the null because of background noise.

RESULTSParticipants

A total of 191 participants successfully completed the run-in period and were randomlyassigned to 1 of the 6 diet sequences. Of them, 162 finished at least 2 of the 3 diet periods andwere eligible for inclusion in the analysis. Drop-out occurrence was distributed evenly acrossthe 3 diets with no one diet proving more difficult to adhere to than the others. Baselinecharacteristics of participants assigned to the 6 diet sequences did not differ. Overall, thepopulation was 55% African American and 44% women, with 74% of women beingpostmenopausal. Mean (±SD) age was 53 ± 10 y and mean body mass index (in kg/m2) was30.4 ± 6.1. Plasma lipids and lipoproteins appeared consistent for a group of this age and obesityfor TGs at 100 ± 67 mg/dL, cholesterol at 206 ± 44 mg/dL, apo B at 84 ± 26 mg/dL, apo C-IIIat 12.7 ± 7.9 mg/dL, and apo E at 7.37 ± 2.76 mg/dL. Adherence to the feeding protocol washigh with participants reporting that on >95% of person-days all study foods were consumedand no nonstudy foods were added. Mean body weight decreased from baseline by 1 kg, andthis change occurred equally across all 3 diets.

Primary outcome: apolipoprotein BTotal plasma apo B was not affected differentially by the 3 diets (Table 2). Compared with theCarb diet, the Prot diet reduced VLDL without apo C-III by 17%, trended toward a 16%reduction in VLDL with apo C-III, and reduced LDL with apo C-III by 16% (Table 3; Figure1). No significant differences were observed in subfraction apo B when the Unsat diet wascompared with the Carb or Prot diets, although the Unsat diet tended to produce concentrationsintermediate between the Carb and Prot diets. Compared with baseline, all 3 diets reducedplasma total apo B by 6−10% (P < 0.05) (Table 2). The reduction in total apo B was mostlydue to a reduction in LDL without apo C-III (8−10%, P < 0.01) (Table 4). Compared withbaseline, the Prot diet reduced very dense LDL (d > 1.063 g/mL) without apo C-III by 14%and total LDL (including the very dense LDL) with apo C-III by 12%. The Prot diet did notchange the concentration of VLDL with apo C-III compared with baseline, whereas it wassignificantly elevated with the Carb and Unsat diets (34% and 25%, respectively).

Secondary outcomesCholesterol and TGs—Compared with the Carb diet, the Prot diet reduced total cholesterolby 4% (Table 2) and cholesterol in LDL without apo C-III by 5% (Table 3). The Prot dietreduced total TGs (9%) and TGs in VLDL with (12%) and without (18%) apo C-III compared



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with the Carb diet (Figure 1). Compared with the Unsat diet, the Prot diet reduced total TGsby 8% and TGs in VLDL with apo C-III by 16%. Compared with baseline, all 3 diets reducedplasma cholesterol by 8−12% (Table 2). The Prot diet reduced total plasma TGs (14%), andthe Unsat diet trended toward reduction of total plasma TGs by 7%, although it was ofborderline significance. All 3 diets reduced cholesterol (9−14%) and TGs (14−17%) in LDLwithout apo C-III (Table 4). Only the Prot diet reduced cholesterol and TG concentrations ofVLDL without apo C-III (18% and 20%, respectively). The Unsat diet increased bothcholesterol and TGs by 20% in VLDL with apo C-III, and a borderline significant trend wasobserved toward an increase of cholesterol in VLDL with apo C-III by the Carb (19%) andProt (15%) diets. TG concentration in LDL with apo C-III was reduced 10% by the Prot diet,and cholesterol concentration was reduced 10−11% by both the Unsat and Prot diets.Lipoprotein lipid composition as determined by molecular ratios of cholesterol and TGs to apoB did not significantly change from baseline or among the diets.

Apolipoproteins C-III and E—Compared with the Carb diet, the Prot diet reduced theconcentration of apo C-III in VLDL by 10% (Table 3). Compared with baseline, the Prot andUnsat diets reduced total plasma apo C-III (9−10%) (Table 2). All 3 diets increased apo C-IIIin VLDL (13−25%). All 3 diets decreased total plasma apo E (8−12%) but increased apo E inVLDL with apo C-III (32−43%) compared with baseline. The Prot and Unsat diets reducedapo E in LDL without apo C-III (9% and 11%, respectively) compared with baseline. Analysisof molecular ratios shows that compared with baseline all 3 diets increased the number ofmolecules of apo C-III contained in each VLDL particle less than they increased the numberof molecules of apo E (Table 4, Figure 2), reducing the ratio of apo C-III to apo E. Thiscompositional change in the particles did not differ among the diets.

DISCUSSIONThe reduction by the Prot diet compared with the Carb diet of apo B in VLDL with apo C-III,apo C-III concentration in VLDL, TGs in VLDL with apo C-III, and overall plasma TGssupports our hypothesis that replacement of carbohydrate will reduce atherogenic TG-richlipoproteins typified by the content of apo C-III. The Unsat diet compared with the Carb diettrended toward similar reductions, but they were not as large and were not statisticallysignificant. It was hypothesized that changes in blood lipids and lipoproteins caused bysubstitution of carbohydrate by unsaturated fat are actually due to carbohydrate reduction andthat protein has an independent effect on plasma lipids which is additive to the effect ofcarbohydrate reduction (19,25). This may explain the qualitatively similar but quantitativelydifferent effects that the Prot and Unsat diets elicited compared with the Carb diet.

Plasma total apo B is a risk factor for CVD, superior to cholesterol concentration (6–8). TheCholesterol and Recurrent Events trial showed that apo B concentration of VLDL is asignificant predictor of recurrent coronary events (9) and that apo B concentration of LDL withapo C-III strongly predicts coronary events in diabetic patients independently of other lipids(11). The Prot diet resulted in a more favorable apo B profile than did the Carb diet throughthe reduction of apo B in VLDL with and without apo C-III and in LDL with apo C-III. Inaddition, results from several studies indicate that apo C-III concentration is a risk factor forCVD (9,11,26,27). Apo C-III concentration was reduced in VLDL by the Prot diet comparedwith the Carb diet, indicating that the Prot diet produces a less atherogenic overall lipoproteinprofile than does the Carb diet. Plasma TGs and apo B are well-established risk factors forCVD (3–8,28–30). Therefore, the Prot diet compared with the Carb diet results in a morefavorable apo B lipoprotein lipid profile in many ways. Generally, the effects of the Unsat dietwere in a similar direction to the Prot diet but less strong.



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Dietary changes from baselineBaseline samples were taken from participants after eating their own free-living diets, whichwere on average higher in saturated fat and cholesterol than the DASH-based OmniHeart diets.Analysis of the overall changes that each diet elicits from baseline approximates the effect thatadherence to these diet patterns will have on a general population of free-living persons.Compared with baseline, all 3 diets lowered whole plasma apo B, primarily through thereduction ofapoBinLDLwithoutapoC-III,themajorapoBparticletype,and the Prot diet reducedLDL particles with apo C-III. Diet studies have found that high-carbohydrate diets increasethe concentration of small, dense LDL (31). In our study the Carb diet increased the most-dense LDL compared with baseline, but the change was not significant. However, the Prot dietreduced small, dense (d < 1.063 g/mL) LDL compared with baseline. The Prot diet also didnot significantly increase apo B in VLDL as the Carb and Unsat diets did. In addition, comparedwith baseline all 3 diets reduced LDL cholesterol, and the Prot diet reduced plasma TGs.Therefore, all 3 diets elicited changes from baseline that are protective against CVD with theProt diet resulting in the most favorable apo B and lipid profiles. The 3 diets increased themolecular ratio of apo E to apo C-III in VLDL with apo C-III by 18−30%, indicating apo Eenrichment after the 3 study diets. Recently, Zheng et al (10) showed that VLDL andintermediate-density lipoprotein (IDL) with both apo C-III and apo E have higher rates ofclearance from plasma than do VLDL and IDL with apo C-III but not apo E, lessening formationof LDL, especially the most atherogenic form with apo C-III. The clearance rate of apo C-III–containing VLDL and IDL is influenced by the ratio of apo C-III to apo E, a lower ratio (ormore apo E relative to apo C-III) producing faster clearance. Thus, the 3 DASH-type dietsimproved the ratio of apo C-III to apo E, a marker for metabolism of VLDL and IDL favorableto reducing CVD risk. Molecular ratios of cholesterol and TGs to apo B did not show significantchanges from baseline or differences between the diets, indicating that the diets alterconcentrations of lipoprotein subtypes but not their lipid composition.

StrengthsThe crossover design of this study allows for a parsimonious analysis with low risk ofconfounding. The sample size was relatively large, and the participants were demographicallyheterogeneous, which strengthens the application of the results to the general US population.We oversampled African Americans, who bear a disproportionate burden of CVD. Risk of biaswas low because of similarly high rates of adherence to and completeness of follow-up afterall 3 of the diets. Changes in lipids and lipoproteins can be attributed to dietary factors becauseother important factors that might elicit these changes were successfully controlled (ie, weight,exercise, and alcohol consumption patterns). Finally, the recommendations stemming fromthis study are easily adopted by the general public because the foods that comprise the dietsare commonlyavailableandmoderatelypricedthroughouttheUnitedStates (24).

LimitationsThe relatively brief duration of each diet period does not allow for assessment of permanenceof lipoprotein changes. However, longer-term studies have shown that changes in blood lipidswill remain as long as the intervention is continued. For the conventional lipid risk factors,plasma total cholesterol and TGs, HDL cholesterol, and LDL cholesterol, the 4-wk results weresimilar to the 6-wk results, suggesting that a new baseline was reached. The controlled dietdesign makes it difficult to gauge the success of long-term adherence to each diet when thediet is chosen by people, essential to continued CVD risk reduction. This study did not addressdietary effects on HDL subpopulations. The Unsat diet increased HDL cholesterol comparedwith the Carb and Prot diets. The Prot diet produced the lowest HDL-cholesterol concentration.



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ConclusionAlthough all 3 diets resulted in changes from baseline in lipoproteins that should reduce CVDrisk, the Prot diet produced the most favorable apo B–containing lipoprotein profile and thelowest plasma total apo B concentration. It also reduced TGs compared with both the Carb andUnsat diets. In fact, the further reduction by the Prot diet compared with the Unsat diet suggestsa TG-lowering effect of protein beyond just replacement of carbohydrate. More importantly,the Prot diet was the most effective at reducing atherogenic apo C-III–containing particles,especially the concentration of LDL with apo C-III. We can estimate the effect of this on CVDby fitting the mean concentration of apo B in apo C-III–containing LDL at baseline and afterthe Prot diet into a relative risk curve from the Cholesterol and Recurrent Events trial (11). Thereduction in LDL with apo C-III after the Prot diet corresponds to a 21% reduced risk ofrecurrent coronary events in persons with diabetes. This projection must be confirmed directlyin other populations. Furthermore, this projection does not take into account the possible effectson CVD of the HDL cholesterol–lowering effect of the Prot diet and the HDL-raising effectof the Unsat diet, as found in OmniHeart (21). Nonetheless, the results that the Prot diet elicitsthe least atherogenic apo B lipoprotein profile combined with the recent report of the superiorityof the Prot diet over the Carb diet in reducing blood pressure (21) makes a strong case forchoosing protein rather than carbohydrate as a replacement for saturated fat to improvecardiovascular health.

Acknowledgements

The author's responsibilities were as follows—JDF: had full access to all study data and takes responsibility for theintegrity of the data and the accuracy of the data analysis; LJA, FMS, VJC, and ERM: study concept and design; JDF,FMS, LJA, VJC, and ERM: acquisition of data; JDF, FMS, VJC, and NL: analyzed and interpreted data; JDF, FMS,and HC: drafted the manuscript; JDF, FMS, HC, LJA, VJC, NL, and ERM: critically revised the manuscript forimportant intellectual content; JDF, FMS, VJC, NL, and HC: provided statistical analysis; LJA and VJC: obtainedfunding; JDF, FMS, LJA, VJC, and NL: provided administrative, technical, or material support; JDF, FMS, LJA, VJC,and EFM: supervised the study. None of the authors had a personal or financial conflict of interest.

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20. Sacks FM, Katan M. Randomized clinical trials on the effects of dietary fat and carbohydrate onplasma lipoproteins and cardiovascular disease. Am J Med 2002;113(suppl 9B):13S–24S. [PubMed:12566134]

21. Appel LJ, Sacks FM, Carey VJ, et al. Effects of protein, monounsatu-rated fat, and carbohydrateintake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA2005;294:2455–64. [PubMed: 16287956]

22. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on theratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of60 controlled trials. Am J Clin Nutr 2003;77:1146–55. [PubMed: 12716665]

23. Obarzanek E, Sacks FM, Vollmer WM, et al. Effects on blood lipids of a blood pressure-loweringdiet: the Dietary Approaches to Stop Hyper-tension (DASH) Trial. Am J Clin Nutr 2001;74:80–9.[PubMed: 11451721]

24. Swain JFMP, Hamilton EF, Sacks FM, Appel LJ. Characteristics of the diet patterns tested in theoptimal macronutrient intake trial to prevent heart disease (OmniHeart): options for a heart-healthydiet. J Am Diet Assoc 2008;108:257–65. [PubMed: 18237574]

25. Parker B, Noakes M, Luscombe N, Clifton P. Effect of a high-protein, high-monounsaturated fatweight loss diet on glycemic control and lipid levels in type 2 diabetes. Diabetes Care 2002;25:425–30. [PubMed: 11874925]

26. Chivot L, Mainard F, Bigot E, et al. Logistic discriminant analysis of lipids and apolipoproteins in apopulation of coronary bypass patients and the significance of apolipoproteins C-III and E.Atherosclerosis 1990;82:205–11. [PubMed: 2375786]



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27. Luc G, Fievet C, Arveiler D, et al. Apolipoproteins C-III and E in apoB-and non-apoB-containinglipoproteins in two populations at contrasting risk for myocardial infarction: the ECTIM study. EtudeCas Temoins sur 'Infarctus du Myocarde. J Lipid Res 1996;37:508–17. [PubMed: 8728314]

28. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular diseaseindependent of high-density lipoprotein cholesterol level: a meta-analysis of population-basedprospective studies. J Cardiovasc Risk 1996;3:213–9. [PubMed: 8836866]

29. Stampfer MJ, Krauss RM, Ma J, et al. A prospective study of triglyceride level, low-densitylipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996;276:882–8. [PubMed:8782637]

30. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158incident cases among 262,525 participants in 29 Western prospective studies. Circulation2007;115:450–8. [PubMed: 17190864]

31. Dreon DM, Fernstrom HA, Miller B, Krauss RM. Low density lipoprotein subclass patterns andlipoprotein response to a reduced fat diet in men. FASEB J 1994;8(1):121–6. [PubMed: 8299884]



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FIGURE 1.Dietary effects on VLDL and LDL with or without apolipoprotein C-III (apo C-III). Percentageof change (mean ± SEM) in apolipoprotein B (apo B; n = 88) in VLDL and LDL with apo C-III and in triglycerides (TGs) (n = 107) in VLDL with and without apo C-III. *Significantlydifferent from baseline measurements, P < 0.05 (paired Student's t test). †Significantly differentfrom the study diet that emphasized carbohydrate (CARB). ‡Significantly different from thestudy diet that emphasized unsaturated fat (UNSAT). PROT indicates the study diet thatemphasized nonmeat protein.



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FIGURE 2.Dietary effects on the ratio of apolipoprotein C-III (apo C-III) to apolipoprotein E (apo E) inapo C-III–containing VLDL. All diets decrease the ratio of apo C-III to apo E in VLDLcompared with baseline. *Significantly different from baseline measurements, P < 0.05 (pairedStudent's t test; n = 147). CARB indicates the study diet that emphasized carbohydrate;UNSAT, the study diet that emphasized unsaturated fats; PROT, the study diet that emphasizednonmeat protein.



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TABLE 1Macronutrient composition of usual and assigned diets1

OmniHeart diets

Baseline usual diet2 CARB PROT UNSAT

Carbohydrate (% of energy) 50 ± 93 58 48 48Fat (% of energy) 31 ± 6 27 27 37 Saturated 11 ± 3 6 6 6 Monounsaturated 13 ± 3 13 13 21 Polyunsaturated 7 ± 2 8 8 10Protein (% of energy) 17 ± 4 15 25 15 Meat 12 ± 4 5.5 9 5.5 Plant and dairy 5 ± 2 9.5 16 9.5

1CARB, study diet that emphasized carbohydrate; PROT, study diet that emphasized nonmeat protein; UNSAT, study diet that emphasized unsaturated

fat.

2Assessed by Willett food-frequency questionnaire (n = 160).

3x̄ ± SD (all such values).


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Furtado et al. Page 14TA

BLE

2B

asel

ine

conc

entra

tions

of w

hole

pla

sma

lipid

s and

lipo

prot

eins

, cha

nges

from

bas

elin

e by

die

t, an

d di

et c

ompa

rison

s1

Cha

nge

from

bas

elin

e by

die

tD

iet c

ompa

riso

ns

Bas

elin

e V

alue

CA

RB

PRO

TU

NSA

TU

NSA

T to

CA

RB

PRO

T to

CA

RB

UN

SAT

to P

RO

T

Val

ueP2

Val

ueP2

Val

ueP2

Val

ueP2

Val

ueP2

Val

ueP2

mg/

dLm

g/dL

mg/

dLm

g/dL

mg/

dLm

g/dL

Cho

lest

erol

(mg/

dL) (

n =

111)

213

± 46

3−1

7 ±

29<

0.01

−25

± 30

< 0.

01−2

2 ±

30<

0.01

−4.6

± 2

60.

06−7

.7 ±

24

< 0.

013.

2 ±

230.

1

Tria

cylg

lyce

rols

(mg/

dL) (

n =

107)

106

± 74

−5.5

± 5

00.

3−1

5 ±

51<

0.01

−7.9

± 4

60.

08−2

.4 ±

45

0.6

−9.5

± 4

20.

027.

1 ±

360.

05

Apo

B (m

g/dL

)(n

= 8

8)83

± 2

8−4

.9 ±

23

0.05

−8.2

± 2

2<

0.01

−6.1

± 2

1<

0.01

−1.2

± 2

10.

6−3

.3 ±

21

0.1

2.1

± 17

0.3

Apo

C-I

II (m

g/dL

) (n

= 11

5)13

.8 ±

8.2

−0.6

7 ±

7.2

0.3

−1.3

± 5

.30.

01−1

.4 ±

6.7

0.03

−0.7

1 ±

5.8

0.2

−0.5

9 ±

5.6

0.3

−0.1

2 ±

4.5

0.8

Apo

E (m

g/dL

)(n

= 1

40)

7.4

± 2.

8−0

.62

± 1.

9<

0.01

−0.8

6 ±

2.3

< 0.

01−0

.88

± 2.

2<

0.01

−0.2

6 ±

1.9

0.1

−0.2

3 ±

1.9

0.2

−0.0

2 ±

1.3

0.8

1 CA

RB

, stu

dy d

iet t

hat e

mph

asiz

ed c

arbo

hydr

ate;

PR

OT,

stud

y di

et th

at e

mph

asiz

ed n

onm

eat p

rote

in; U

NSA

T, st

udy

diet

that

em

phas

ized

uns

atur

ated

fat;

apo

B, a

polip

opro

tein

B; a

po C

-III

,ap

olip

opro

tein

C-I

II, a

po E

, apo

lipop

rote

in E

.

2 Det

erm

ined

by

paire

d St

uden

t's t

test

with

sign

ifica

nce

defin

ed a

s P ≤

0.0

5.

3 x̄ +

SD (a

ll su

ch v

alue

s).


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BLE

3D

iffer

ence

s bet

wee

n di

ets i

n pl

asm

a lip

opro

tein

subf

ract

ions

1

UN

SAT

to C

AR

BPR

OT

to C

AR

BU

NSA

T to

PR

OT

Val

ueP2

Val

ueP2

Val

ueP2

mg/

dLm

g/dL

mg/

dLLi

popr

otei

ns w

ith a

po C

-III

V

LDL

Cho

lest

erol

(n =

111

)0.

06 ±

5.4

30.

9−0

.16

± 4.

60.

70.

21 ±

4.0

0.6

Tria

cylg

lyce

rols

(n =

107

)0.

68 ±

15

0.6

−2.0

± 1

20.

052.

7 ±

130.

02

A

po B

(n =

88)

−0.0

9 ±

0.98

0.4

−0.2

0 ±

1.0

0.07

0.11

± 0

.86

0.2

Apo

C-I

II (n

= 1

18)

−0.1

1 ±

0.76

0.1

−0.1

7 ±

0.8

0.03

0.06

± 0

.84

0.5

Apo

E (n

= 1

40)

−0.0

2 ±

0.33

0.5

−0.0

3 ±

0.30

0.2

0.01

± 0

.37

0.7

L

DL

Cho

lest

erol

(n =

111

)−0

.78

± 5.

70.

2−0

.89

± 6.

50.

20.

11 ±

5.0

0.8

Tria

cylg

lyce

rols

(n =

107

)−0

.32

± 5.

10.

5−0

.61

± 4.

90.

20.

29 ±

4.1

0.4

Apo

B4 (n

= 8

8)−0

.55

± 5.

00.

31.

2 ±

5.6

0.04

0.69

± 3

.80.

1

A

po C

-III

(n =

118

)−0

.1 ±

0.6

90.

1−0

.11

± 0.

650.

070.

01 ±

0.6

90.

9

A

po E

(n =

140

)−0

.002

± 0

.18

0.9

0.00

2 ±

0.20

0.9

−0.0

04 ±

0.1

90.

8

Ver

y de

nse

LDL

(d >

1.0

63 g

/mL)

Apo

B (n

= 8

8)−0

.06

± 0.

70.

5−0

.12

± 0.

80.

20.

06 ±

0.4

0.2

Lipo

prot

eins

with

out a

po C

-III

V

LDL

Cho

lest

erol

(n =

111

)−0

.40

± 8.

10.

6−1

.4 ±

9.4

0.1

0.96

± 7

.20.

2

T

riacy

lgly

cero

ls (n

= 1

07)

−2.2

± 2

60.

3−5

.7 ±

32

0.05

3.4

± 23

0.1

Apo

B (n

= 8

8)−0

.30

± 2.

10.

2−0

.49

± 2.

20.

030.

2 ±

1.6

0.3

Apo

E (n

= 1

40)

−0.0

2 ±

0.17

0.1

−0.0

1 ±

0.15

0.6

−0.0

2 ±

0.16

0.2

L

DL

Cho

lest

erol

(n =

111

)−3

.0 ±

20

0.1

−5.2

± 1

7<

0.01

2.2

± 18

0.2

Tria

cylg

lyce

rols

(n =

107

)−0

.56

± 14

0.7

−0.7

3 ±

9.4

0.4

0.17

± 1

10.

9

A

po B

4 (n =

88)

0.26

± 1

70.

9−1

.4 ±

18

0.5

1.1

± 15

0.5

Apo

E (n

= 1

40)

−0.0

2 ±

0.18

0.2

−0.0

1 ±

0.15

0.3

−0.0

1 ±

0.16

0.5

V

ery

dens

e LD

L (d

> 1

.063

g/m

L)

A

po B

(n =

88)

−0.6

3 ±

4.0

0.1

−0.8

5 ±

4.3

0.07

0.22

± 3

.30.

5

1 UN

SAT,

stud

y di

et th

at e

mph

asiz

ed u

nsat

urat

ed fa

t; C

AR

B, s

tudy

die

t tha

t em

phas

ized

car

bohy

drat

e; P

RO

T, st

udy

diet

that

em

phas

ized

non

mea

t pro

tein

; apo

B, a

polip

opro

tein

B, a

po C

-III

,ap

olip

opro

tein

C-I

II, a

po E

, apo

lipop

rote

in E

; d, d

ensi

ty. B

asel

ine

valu

es a

re sh

own

in T

able

4.

2 Det

erm

ined

by

paire

d St

uden

t's t

test

with

sign

ifica

nce

defin

ed a

s P ≤

0.0

5.

3 x̄ ±

SD (a

ll su

ch v

alue

s).

4 Incl

udes

apo

B fo

und

at d

> 1

.063

g/m

L.


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BLE

4B

asel

ine

conc

entra

tions

of p

lasm

a lip

opro

tein

subf

ract

ions

and

cha

nges

from

bas

elin

e by

die

t1

Cha

nge

from

bas

elin

e by

die

t

CA

RB

PRO

TU

NSA

T

Bas

elin

eV

alue

P2V

alue

P2V

alue

P2

mg/

dLm

g/dL

mg/

dLm

g/dL

Lipo

prot

eins

with

apo

C-I

II

VLD

L

C

hole

ster

ol (n

= 1

11)

4.4

± 4.

230.

84 ±

4.6

0.06

0.68

± 3

.70.

060.

89 ±

4.3

0.03

Tria

cylg

lyce

rols

(n =

107

)17

± 1

62.

5 ±

160.

080.

50 ±

15

0.7

3.2

± 17

0.04

Apo

B (n

= 8

8)0.

94 ±

0.8

70.

32 ±

1.0

9<

0.01

0.12

± 0

.79

0.2

0.23

± 0

.96

0.03

Apo

C-I

II (n

= 1

18)

1.3

± 1.

10.

31 ±

0.9

0<

0.01

0.14

± 0

.87

0.1

0.20

± 0

.85

0.02

Apo

E (n

= 1

40)

0.31

± 0

.27

0.13

± 0

.35

< 0.

010.

10 ±

0.3

9<

0.01

0.11

± 0

.36

< 0.

01

LD

L

C

hole

ster

ol (n

= 1

11)

12 ±

10

−0.5

3 ±

5.9

0.4

−1.4

± 6

.50.

02−1

.3 ±

6.2

0.03

Tria

cylg

lyce

rols

(n =

107

)10

± 7

.6−0

.45

± 6.

70.

5−1

.06

± 6.

10.

05−0

.77

± 5.

50.

1

A

po B

4 (n =

88)

7.7

± 6.

30.

36 ±

6.1

0.6

−0.8

8 ±

4.3

0.06

−0.1

9 ±

4.4

0.7

Apo

C-I

II (n

= 1

18)

1.7

± 1.

10.

06 ±

0.6

30.

4−0

.06

± 0.

610.

3−0

.05

± 0.

730.

5

A

po E

(n =

140

)0.

39 ±

0.2

9−0

.001

± 0

.18

0.9

0.00

3 ±

0.18

0.9

0.00

1 ±

0.16

0.9

V

ery

dens

e LD

L (d

> 1

.063

g/m

L)

A

po B

(n =

88)

0.98

± 0

.89

−0.0

2 ±

0.99

0.9

−0.1

3 ±

0.78

0.1

−0.0

7 ±

0.67

0.3

Lipo

prot

eins

with

out a

po C

-III

V

LDL

Cho

lest

erol

(n =

111

)11

± 9

−0.6

2 ±

8.2

0.4

−2.0

± 8

.90.

02−1

.0 ±

8.3

0.2

Tria

cylg

lyce

rols

(n =

107

)33

± 4

1−1

.0 ±

29

0.7

−6.7

± 2

90.

01−3

.3 ±

24

0.1

Apo

B (n

= 8

8)2.

7 ±

2.2

0.20

± 2

.20.

4−0

.30

± 1.

60.

8−0

.10

± 1.

50.

5

A

po E

(n =

140

)0.

21 ±

0.2

20.

006

± 0.

220.

80.

000

± 0.

200.

9−0

.02

± 0.

150.

2

LD

L

C

hole

ster

ol (n

= 1

11)

119

± 36

−11

± 22

< 0.

01−1

6 ±

23<

0.01

−14

± 25

< 0.

01

T

riacy

lgly

cero

ls (n

= 1

07)

29 ±

16

−4.2

± 1

7<

0.01

−5.0

± 1

5<

0.01

−4.8

± 1

7<

0.01

Apo

B4 (n

= 8

8)71

± 2

3−5

.7 ±

20

< 0.

01−7

.1 ±

19

< 0.

01−6

.0 ±

17

< 0.

01

A

po E

(n =

140

)0.

40 ±

0.2

4−0

.02

± 0.

160.

09−0

.04

± 0.

16<

0.01

−0.0

5 ±

0.16

< 0.

01

Ver

y de

nse

LDL

(d >

1.0

63 g

/mL)

Apo

B (n

= 8

8)5.

7 ±

5.0

0.03

± 4

.50.

9−0

.82

± 2.

8<

0.01

−0.6

0 ±

3.9

−0.2

1 CA

RB

, stu

dy d

iet t

hat e

mph

asiz

ed c

arbo

hydr

ate;

PR

OT,

stud

y di

et th

at e

mph

asiz

ed n

onm

eat p

rote

in; U

NSA

T, st

udy

diet

that

em

phas

ized

uns

atur

ated

fat;

apo

C-I

II, a

polip

opro

tein

C-I

II; a

po B

,ap

olip

opro

tein

B, a

po E

, apo

lipop

rote

in E

; d, d

ensi

ty.

2 Det

erm

ined

by

paire

d St

uden

t's t

test

with

sign

ifica

nce

defin

ed a

s P ≤

0.0

5.

3 x̄ ±

SD (a

ll su

ch v

alue

s).

4 Incl

udes

apo

B fo

und

at d

> 1

.063

g/m

L.


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Effect of protein, unsaturated fat, and carbohydrate intakes on plasma apolipoprotein B and VLDL and...

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